Inhibition of autophagy promotes metastasis and glycolysis by inducing ROS in gastric cancer cells

Abstract

Autophagy defect has been shown to be correlated with malignant phenotype and poor prognosis of human cancers, however, the detailed mechanisms remain obscure. In this study, we investigated the biological changes induced by autophagy inhibition in gastric cancer. We showed that inhibition of autophagy in gastric cancer cells promotes epithelial-mesenchymal transition (EMT) and metastasis, alters metabolic phenotype from mitochondrial oxidative phosphorylation to aerobic glycolysis and converts cell phenotype toward malignant, which maybe further contribute to chemoresistance and poor prognosis of gastric cancer. We also identified that the EMT and metabolism alterations induced by autophagy inhibition were dependent on ROS-NF-κB-HIF-1α pathway. More importantly, scavenging of ROS by the antioxidant N-acetylcysteine (NAC) attenuated activation of NF-κB and HIF-1α in autophagydeficient gastric cancer cells, and autophagy inhibition induced metastasis and glycolysis were also diminished by NAC in vivo. Taken together, our findings suggested that autophagy defect promotes metastasis and glycolysis of gastric cancer, and antioxidants could be used to improve disease outcome for gastric cancer patients with autophagy defect.

The Prognostic Role of SIRT1-Autophagy Axis in Gastric Cancer

“…Furthermore, it has been demonstrated that acetylation of Beclin-1 can lead to inhibition of autophagic responses [23]. Indeed, knockdown of Beclin-1 in GC cells results in inhibition of autophagy, which in turn promotes EMT and metastasis [29]. Immunohistochemistry is another indispensable tool for the evaluation of autophagy in situ [30].…”

Introductory Chapter: Overview on Autophagy in Burden of Functions

“…Moreover, at cellular level these barriers represent numerous interfaces of tissues and organs with ambient and internal environment to sustain structural, immune and metabolic integrity. From this perspective, while macroautophagy, microphagy and chaperone-mediated autophagy execute barrier functions at molecular and membrane levels [2,5,6,[13][14][15][16][17], it would be reasonable to assume that dynamics and efficacy of autophagy function can determine performance of the barrierforming cells. Note, in the vertebrates the infection cellular barriers are constituted by multidimensional interactive networks of mesenchymal, epithelial, reticuloendothelial, endothelial and hematopoietic cells, where along with monocytes and polymorphonuclear granulocytes, a particular role in xenobiotic control and "cleaning function" is attributed to nonprofessional phagocytes, e.g., skin fibroblasts, bone marrow stromal cells, endothelial and epithelial cells [18,19].…”

“…That infers increasing burden of autophagy function in nonprofessional phagocytes when professional phagocytes are depleted due to pathological conditions. Furthermore, considering that nonprofessional phagocytes can also orchestrate response to acute stress or trauma by expression and massive release of paracrine and endocrine factors, such as damage-associated molecular patterns (DAMPs), inflammatory cytokines, proteases, chemokines, defensins, nitric oxide, ROS, fragmented DNA, exosomes and microvesicles, which in turn can trigger and propagate autophagy stress response [6,[14][15][16][17][18][19].…”

“…are all borne by the highly conserved ATG-genes, Atg-proteins as well as by several signaling modules (e.g., mTOR, AMPK, the PI3K complexes, CREB transcriptional factor), sequestosome 1/p62-like receptors -adaptor proteins (e.g., p62/SQSTM1, NBR1, NDP52, T6BP, optineurin) and quality control modifiers (e.g., ubiquitins, galectins, STING) [1, 2, 5-7, 10, 11, 13, 16 and current book Chpts. 2,3,16,17,21]. In conjunction with this, interestingly that "membrane structural modules" arranged by mitochondria and endoplasmic reticulum (or the ER-mitochondrial axes), which are other key players in cell bioenergetics and proteostasis, are also involved in the emerging macroautophagy signaling mechanisms [5,6,12,13].…”

“…3, 14, 22]. These observations link impairment of autophagy machinery with pathogenesis of severe degenerative diseases and with promotion of aging, chronic viral infections and tumorigenesis, but also tumor cell death [11][12][13][14]17], current book Chpts. 3,14,22].…”